Hypothalamic Signaling Mechanisms in Hypertension

  • Casey Y. Carmichael
  • Richard D. WainfordEmail author
Hypertension and the Brain (S Stocker, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Hypertension and the Brain


The etiology of hypertension, a critical public health issue affecting one in three US adults, involves the integration of the actions of multiple organ systems, including the central nervous system. Increased activation of the central nervous system, driving enhanced sympathetic outflow and increased blood pressure, has emerged as a major contributor to the pathogenesis of hypertension. The hypothalamus is a key brain site acting to integrate central and peripheral inputs to ultimately impact blood pressure in multiple disease states that evoke hypertension. This review highlights recent advances that have identified novel signal transduction mechanisms within multiple hypothalamic nuclei (e.g., paraventricular nucleus, arcuate nucleus) acting to drive the pathophysiology of hypertension in neurogenic hypertension, angiotensin II hypertension, salt-sensitive hypertension, chronic intermittent hypoxia, and obesity-induced hypertension. Increased understanding of hypothalamic activity in hypertension has the potential to identify novel targets for future therapeutic interventions designed to treat hypertension.


Hypothalamus Hypertension Signal transduction Paraventricular nucleus Arcuate nucleus Hypertension Autonomic control 



This work was supported by NIH grants R01HL107330 and K02HL112718 to RDW.

Compliance with Ethics Guidelines

Conflict of Interest Casey Y. Carmichael and Richard D. Wainford declare no conflicts of interest.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131(4):e29–e322.PubMedGoogle Scholar
  2. 2.
    DiBona GF. Sympathetic nervous system and hypertension. Hypertension. 2013;61(3):556–60.PubMedGoogle Scholar
  3. 3.
    Hirooka Y, Kishi T, Ito K, Sunagawa K. Potential clinical application of recently discovered brain mechanisms involved in hypertension. Hypertension. 2013;62(6):995–1002.PubMedGoogle Scholar
  4. 4.
    Parati G, Esler M. The human sympathetic nervous system: its relevance in hypertension and heart failure. Eur Heart J. 2012;33(9):1058–66. doi: Scholar
  5. 5.
    Ye ZY, Li DP, Byun HS, Li L, Pan HL. NKCC1 upregulation disrupts chloride homeostasis in the hypothalamus and increases neuronal activity-sympathetic drive in hypertension. J Neurosci. 2012;32(25):8560–8.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Ye ZY, Li DP, Pan HL. Regulation of hypothalamic presympathetic neurons and sympathetic outflow by group II metabotropic glutamate receptors in spontaneously hypertensive rats. Hypertension. 2013;62(2):255–62.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Li DP, Zhu LH, Pachuau J, Lee HA, Pan HL. mGluR5 upregulation increases excitability of hypothalamic presympathetic neurons through NMDA receptor trafficking in spontaneously hypertensive rats. J Neurosci. 2014;34(12):4309–17.PubMedGoogle Scholar
  8. 8.
    Stern JE, Sonner PM, Son SJ, Silva FC, Jackson K, Michelini LC. Exercise training normalizes an increased neuronal excitability of NTS-projecting neurons of the hypothalamic paraventricular nucleus in hypertensive rats. J Neurophysiol. 2012;107(10):2912–21.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Davern PJ, Chowdhury S, Jackson KL, Nguyen-Huu TP, Head GA. GABAA receptor dysfunction contributes to high blood pressure and exaggerated response to stress in Schlager genetically hypertensive mice. J Hypertens. 2014;32(2):352–62.PubMedGoogle Scholar
  10. 10.
    Li DP, Byan HS, Pan HL. Switch to glutamate receptor 2-lacking AMPA receptors increases neuronal excitability in hypothalamus and sympathetic drive in hypertension. J Neurosci. 2012;32(1):372–80.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Ye ZY, Li L, Li DP, Pan HL. Casein kinase 2-mediated synaptic GluN2A up-regulation increases N-methyl-D-aspartate receptor activity and excitability of hypothalamic neurons in hypertension. JBC. 2012;287(21):17438–46.Google Scholar
  12. 12.
    Pachuau J, Li DP, Chen SR, Lee HA, Pan HL. Protein kinase CK2 contributes to diminished small conductance Ca2 + -activated K+ channel activity of hypothalamic pre-sympathetic neurons in hypertension. J Neurochem. 2014;130(5):657–67.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Kawabe T, Kawabe K, Sapru HN. Cardiovascular responses to chemical stimulation of the hypothalamic arcuate nucleus in the rat: role of the hypothalamic paraventricular nucleus. PLoS One. 2012;7(9):e45180.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Kawabe T, Kawabe K, Sapru HN. Effect of barodenervation on cardiovascular responses elicited from the hypothalamic arcuate nucleus of the rat. PLoS One. 2012;7(12):e53111.PubMedPubMedCentralGoogle Scholar
  15. 15.•
    Kawabe T, Kawabe K, Sapru HN. Tonic gamma-aminobutyric acid-ergic activity in the hypothalamic arcuate nucleus is attenuated in the spontaneously hypertensive rat. Hypertension. 2013;62(2):281–7. This report provides the first documentation that imparied hypothalamic arcuate nucleus signaling contributes to the pathophysiology of hypertension in the spontaneosly hypertensive rat. The impact of arcuate nucleus signaling in other forms of hypertension remains to be established but potentially represents new hypertensive hypothalamic signaling paradigm.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Qi J, Zhang DM, Suo YP, Song XA, Yu XJ, Elks C, et al. Renin-angiotensin system modulates neurotransmitters in the paraventricular nucleus and contributes to angiotensin II-induced hypertensive response. Cardiovasc Toxicol. 2013;13(1):48–54.PubMedGoogle Scholar
  17. 17.
    Cardinale JP, Sriramula S, Mariappan N, Agarwal D, Francis J. Angiotensin II-induced hypertension is modulated by nuclear factor-kappaB in the paraventricular nucleus. Hypertension. 2012;59(1):113–21.PubMedGoogle Scholar
  18. 18.
    Sriramula S, Xia H, Xu P, Lazartigues E. Brain-targeted angiotensin-converting enzyme 2 overexpression attenuates neurogenic hypertension by inhibiting cyclooxygenase-mediated inflammation. Hypertension. 2014. doi: Scholar
  19. 19.
    Su Q, Qin DN, Wang FX, Ren J, Li HB, Zhang M, et al. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin-angiotensin system and proinflammatory cytokines in hypertension. Toxicol Appl Pharmacol. 2014;276(2):115–20.PubMedGoogle Scholar
  20. 20.
    Yu Y, Xue BJ, Zhang ZH, Wei SG, Beltz TG, Guo F, et al. Early interference with p44/42 mitogen-activated protein kinase signaling in hypothalamic paraventricular nucleus attenuates angiotensin II-induced hypertension. Hypertension. 2013;61(4):842–9.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Shi P, Grobe JL, Desland FA, Zhou G, Shen XZ, Shan Z, et al. Direct pro-inflammatory effects of prorenin on microglia. PLoS One. 2014;9(10):e92937. This report.PubMedPubMedCentralGoogle Scholar
  22. 22.
    de Kloet AD, Pati D, Wang L, Hiller H, Sumners C, Frazier CJ, et al. Angiotensin type 1a receptors in the paraventricular nucleus of the hypothalamus protect against diet-induced obesity. J Neurosci. 2013;33(11):4825–33.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Bardgett ME, Holbein WW, Herrera-Rosales M, Toney GM. Ang II-salt hypertension depends on neuronal activity in the hypothalamic paraventricular nucleus but not on local actions of tumor necrosis factor-alpha. Hypertension. 2014;63(3):527–34.PubMedGoogle Scholar
  24. 24.
    Yuan N, Zhang F, Zhang LL, Gao J, Zhou YB, Han Y, et al. SOD1 gene transfer into paraventricular nucleus attenuates hypertension and sympathetic activity in spontaneously hypertensive rats. Pflugers Arch. 2013;465(2):261–70.PubMedGoogle Scholar
  25. 25.
    Coleman CG, Wang G, Faraco G, Marques Lopes J, Waters EM, Milner TA, et al. Membrane trafficking of NADPH oxidase p47(phox) in paraventricular hypothalamic neurons parallels local free radical production in angiotensin II slow-pressor hypertension. J Neurosci. 2013;33(10):4308–16.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Northcott CA, Billecke S, Craig T, Hinojosa-Laborde C, Patel KP, Chen AF, et al. Nitric oxide synthase, ADMA, SDMA, and nitric oxide activity in the paraventricular nucleus throughout the etiology of renal wrap hypertension. Am J Physiol Heart Circ Physiol. 2012;302(11):H2276–84.PubMedPubMedCentralGoogle Scholar
  27. 27.
    Zhou YB, Sun HJ, Chen D, Liu TY, Han Y, Wang JJ, et al. Intermedin in paraventricular nucleus attenuates sympathetic activity and blood pressure via nitric oxide in hypertensive rats. Hypertension. 2014;63(2):330–7.PubMedGoogle Scholar
  28. 28.
    Yi SS, Kim HJ, Do SG, Lee YB, Ahn HJ, Hwang IK, et al. Arginine vasopressin (AVP) expressional changes in the hypothalamic paraventricular and supraoptic nuclei of stroke-prone spontaneously hypertensive rats. Anat Cell Biol. 2012;45(2):114–20.PubMedPubMedCentralGoogle Scholar
  29. 29.
    Pietranera L, Brocca ME, Cymeryng C, Gomez-Sanchez E, Gomez-Sanchez CE, Roig P, et al. Increased expression of the mineralocorticoid receptor in the brain of spontaneously hypertensive rats. J Neuroendocrinol. 2012;24(9):1249–58.PubMedGoogle Scholar
  30. 30.
    Chen A, Huang BS, Wang HW, Ahmad M, Leenen FH. Knockdown of mineralocorticoid or angiotensin II type 1 receptor gene expression in the paraventricular nucleus prevents angiotensin II hypertension in rats. J Physiol. 2014;592(Pt 16):3523–36.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Kim YB, Kim YS, Kim WB, Shen FY, Lee SW, Chung HJ, et al. GABAergic excitation of vasopressin neurons: possible mechanism underlying sodium-dependent hypertension. Circ Res. 2013;113(12):1296–307.PubMedGoogle Scholar
  32. 32.•
    Choe KY, Han SY, Gaub P, Shell B, Voisin DL, Knapp BA, et al. High salt intake increases blood pressure via BDNF-mediated downregulation of KCC2 and impaired baroreflex inhibition of vasopressin neurons. Neuron. 2015;85(3):549–60. This report reveals a novel action of brain derived neurotrphic factor to downregulate KCC2 to abolish aortic barorecepetor evoked GABAergic inhibition of hypothalamic AVP neurons during sodium challenge. Significantly, this study demonstrates altered GABAergic inputs to hypothalamic AVP neurons drives excess AVP release to evoke hypertension via a peripheral V1 receptor mediated vasoconstrictor mechanism. These studies clearly reveal the impact of excess AVP release on the pathophysiology of salt-sensitive hypertension.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Whelton PK, Appel LJ, Sacco RL, Anderson CA, Antman EM, Campbell N, et al. Sodium, blood pressure, and cardiovascular disease: further evidence supporting the American Heart Association sodium reduction recommendations. Circulation. 2012;126(24):2880–9.PubMedGoogle Scholar
  34. 34.
    Kotchen TA, Cowley Jr AW, Frohlich ED. Salt in health and disease—a delicate balance. New Eng J Med. 2013;368(13):1229–37.PubMedGoogle Scholar
  35. 35.
    Huang BS, White RA, Leenen FH. Possible role of brain salt-inducible kinase 1 in responses to central sodium in Dahl rats. Am J Physiol Reg Integr Comp Physiol. 2012;303(2):R236–45.Google Scholar
  36. 36.
    Gabor A, Leenen FH. Central mineralocorticoid receptors and the role of angiotensin II and glutamate in the paraventricular nucleus of rats with angiotensin II-induced hypertension. Hypertension. 2013;61(5):1083–90.PubMedGoogle Scholar
  37. 37.
    Holbein WW, Toney GM. Activation of the hypothalamic paraventricular nucleus by forebrain hypertonicity selectively increases tonic vasomotor sympathetic nerve activity. Am J Physiol Reg Integr Comp Physiol. 2014. doi: Scholar
  38. 38.
    Simmonds SS, Lay J, Stocker SD. Dietary salt intake exaggerates sympathetic reflexes and increases blood pressure variability in normotensive rats. Hypertension. 2014;64(3):583–9.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Kapusta DR, Pascale CL, Wainford RD. Brain heterotrimeric Galphai(2)-subunit protein-gated pathways mediate central sympathoinhibition to maintain fluid and electrolyte homeostasis during stress. FASEB J. 2012;26(7):2776–87.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Kapusta DR, Pascale CL, Kuwabara JT, Wainford RD. Central nervous system Galphai2-subunit proteins maintain salt resistance via a renal nerve-dependent sympathoinhibitory pathway. Hypertension. 2013;61(2):368–75.PubMedGoogle Scholar
  41. 41.
    Wainford RD, Carmichael CY, Pascale CL, Kuwabara JT. Galphai2-protein-mediated signal transduction: central nervous system molecular mechanism countering the development of sodium-dependent hypertension. Hypertension. 2015;65(1):178–86.PubMedGoogle Scholar
  42. 42.
    Knight WD, Saxena A, Shell B, Nedungadi TP, Mifflin SW, Cunningham JT. Central losartan attenuates increases in arterial pressure and expression of FosB/DeltaFosB along the autonomic axis associated with chronic intermittent hypoxia. Am J Physiol Reg Integr Comp Physiol. 2013;305(9):R1051–8.Google Scholar
  43. 43.
    Sharpe AL, Calderon AS, Andrade MA, Cunningham JT, Mifflin SW, Toney GM. Chronic intermittent hypoxia increases sympathetic control of blood pressure: role of neuronal activity in the hypothalamic paraventricular nucleus. Am J Physiol Heart Circ Physiol. 2013;305(12):H1772–80.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Dergacheva O, Dyavanapalli J, Pinol RA, Mendelowitz D. Chronic intermittent hypoxia and hypercapnia inhibit the hypothalamic paraventricular nucleus neurotransmission to parasympathetic cardiac neurons in the brain stem. Hypertension. 2014;64(3):597–603.PubMedPubMedCentralGoogle Scholar
  45. 45.
    Fatouleh RH, Hammam E, Lundblad LC, Macey PM, McKenzie DK, Henderson LA, et al. Functional and structural changes in the brain associated with the increase in muscle sympathetic nerve activity in obstructive sleep apnoea. NeuroImage Clin. 2014;6:275–83.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Tanida M, Yamamoto N, Shibamoto T, Rahmouni K. Involvement of hypothalamic AMP-activated protein kinase in leptin-induced sympathetic nerve activation. PLoS One. 2013;8(2):e56660.PubMedPubMedCentralGoogle Scholar
  47. 47.•
    Harlan SM, Guo DF, Morgan DA, Fernandes-Santos C, Rahmouni K. Hypothalamic mTORC1 signaling controls sympathetic nerve activity and arterial pressure and mediates leptin effects. Cell Metab. 2013;17(4):599–606. This report demonstrates in obesity-induced hypertension leptin activates mTORC1 via a PI3K pathway and that mTORC1 activity is required to mediate leptin induced increases in renal sympathetic nerve activity and blood pressure. The locus of this action has been identified as the hypothalamic ARCN as ARCN blockade of mTORC1 signaling essentially eliminates leptin evoked hypertension and renal sympathoexcitation.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Shi Z, Brooks VL. Leptin differentially increases sympathetic nerve activity and its baroreflex regulation in female rats: role of estrogen. J Physiol. 2014. doi: Scholar
  49. 49.
    Prior LJ, Davern PJ, Burke SL, Lim K, Armitage JA, Head GA. Exposure to a high-fat diet during development alters leptin and ghrelin sensitivity and elevates renal sympathetic nerve activity and arterial pressure in rabbits. Hypertension. 2014;63(2):338–45.PubMedGoogle Scholar
  50. 50.
    Luckett BS, Frielle JL, Wolfgang L, Stocker SD. Arcuate nucleus injection of an anti-insulin affibody prevents the sympathetic response to insulin. Am J Physiol Heart Circ Physiol. 2013;304(11):H1538–46.PubMedPubMedCentralGoogle Scholar
  51. 51.
    Stocker SD, Gordon KW. Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation. J Neurophysiol. 2014. doi: Scholar
  52. 52.
    Steiner JL, Bardgett ME, Wolfgang L, Lang CH, Stocker SD. Glucocorticoids attenuate the central sympathoexcitatory actions of insulin. J Neurophysiol. 2014;112(10):2597–604.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Muta K, Morgan DA, Rahmouni K. The role of hypothalamic mTORC1 signaling in insulin regulation of food intake, body weight and sympathetic nerve activity in male mice. Endocrinology. 2015. doi: Scholar
  54. 54.••
    Biancardi VC, Son SJ, Ahmadi S, Filosa JA, Stern JE. Circulating angiotensin II gains access to the hypothalamus and brain stem during hypertension via breakdown of the blood–brain barrier. Hypertension. 2014;63(3):572–9. This paper reveals for the first time that circulating Ang II, under hypertensive conditions, exerts direct actions in the brain, specifically in the hypothalamus. These studies reveal in the spontaneously hypertensive rat Ang II impairs the integrity of the blood brain barrier in the hypothalamic region via an AT1R mechanism, facilitating increased Ang II levels and Ang II co-localization with neurons and glial in the PVN.PubMedGoogle Scholar
  55. 55.••
    Xue B, Zhang Z, Johnson RF, Johnson AK. Sensitization of slow pressor angiotensin II (Ang II)-initiated hypertension: induction of sensitization by prior Ang II treatment. Hypertension. 2012;59(2):459–66. This paper reports the impact of central nervous system sensitization on the pathogenesis of Ang II slow pressor hypertension in which prior sensitization with non-pressor Ang II exacerbates the subsequent hypertensive response to slow pressor Ang II infusion. These data highlight the impact of hypothalamic sensitization on the pathophysiology of hypertension—a phenomenon that may have important implications for the central regulation of blood pressure.PubMedPubMedCentralGoogle Scholar
  56. 56.••
    Mittag J, Lyons DJ, Sallstrom J, Vujovic M, Dudazy-Gralla S, Warner A, et al. Thyroid hormone is required for hypothalamic neurons regulating cardiovascular functions. J Clin Invest. 2013;123(1):509–16. This publication identifies a previously unknown population of parvalbuminergic neurons in the anterior hypothalamus, which require thyroid hormone signaling for correct development. Significantly, this neuronal population has a profound impact on blood pressure regulation as ablation of these cells evokes hypertension via alteration is central autonomic function. Future studies are required to establish the impact of this neuronal population in the pathophysiology of hypertension.PubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Pharmacology & Experimental Therapeutics and The Whitaker Cardiovascular InstituteBoston University School of MedicineBostonUSA

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